This issue of Myeloma Today is sponsored in part by an unrestricted educational grant from Novartis Pharmaceuticals.

Myeloma Today (UK): Please tell us a little about yourself. Where did you study and how did you become interested in proteasome inhibitors?

Dr. Julian Adams: I was recruited to a startup biotech company, Myogenics (which changed its name to ProScript), started by Alfred Goldberg, Tom Maniatis, Michael Rosenblatt, and Kenneth Rock, all Professors at Harvard in 1994. I had been working in established pharmaceutical companies for 12 years and had successfully discovered drugs, notably Viramune, for HIV. There were a series of key discoveries in the Maniatis, Goldberg, and Rock labs, about the role of the proteasome in cellular biology that I found absolutely fascinating, so I thought this might be a tremendous new opportunity for drug discovery.

MT (UK): What is your research history? What other drugs/treatments have you worked on previously?

Dr. Adams: I started my career at Merck Frosst in Canada working in drug discovery for asthma. I moved to Boehringer Ingelheim to work on HIV during 1989-94.

MT (UK): When did it become apparent that you were on to a potential exciting breakthrough?

Dr. Adams: We had discovered a very potent inhibitor of the proteasome in our labs, which eventually led to Velcade (or PS-341, as it was then called) in the fall of 1994. It was about one year later that we did our first proof of concept study in cancer in a collaboration with Beverly Teicher at Harvard. We showed that we could inhibit tumor growth in a mouse model of lung cancer. I became convinced at that point that we had a viable treatment, but we still didnt know how best to use the drug. What dose and schedule would be optimal? Would it be safe enough? We spent about two more years figuring the details out in laboratory studies.

MT (UK): How difficult was it to get VELCADE from the bench to the bed, as it were?

Dr. Adams: Incredibly tough! Early on in its development no one believed in the molecule, or the target! It was assumed that this approach would lead to overwhelming toxicity. Many needed to be convinced. Our own employees at ProScript were skeptical, the scientific founders, the Board of Directors, all in the company. As for the outside world, it was next to impossible. David Livingston, of the Dana Farber Cancer Institute, joined our scientific board and helped me enormously in changing the views within the company. I also forged a formidable alliance with the National Cancer Institute, who was also initially skeptical, but under the guidance of Edward Sausville at the NCI, we kept building the evidence for a case to see VELCADE through. After completing rigorous pre-clinical studies, especially safety studies, we presented to a committee at the NCI (Chaired by Sausville) and won unanimous approval to begin to prepare the phase I program. In parallel, I sought assistance from CapCURE, a prostate cancer foundation, who funded Christopher Logothetis, Chairman of Genitourinary Oncology at the MD Anderson Cancer Center, and we began our first trial in October 1998. Things really took off when we were eventually acquired by Millennium in 1999. The members of the oncology franchise are a unique and fantastically talented group of people. At Millennium, VELCADE was adopted at a professional level with the resources and budget to really drive the scientific and medical program.

MT (UK): What do you think were the key elements in being able to achieve this?

Dr. Adams: The data, the data, the data, and tons of stubborn perseverance on the part of my team. Peter Elliott was the project leader and as tenacious as ever at driving us forward. In the end Sausville at NCI, Howard Soule at CapCURE, and Chris Logothetis took a chance on PS-341 and I am eternally indebted to those brave souls. Make no mistake though, the data won the day! At Millennium this was well recognised by the management team, led by Mark Levin, and they with the oncology team came together to make VELCADE a priority and drive the program towards the successful registration.

Eventually, our phase I studies, in a trial led by Dr. Robert Orlowski at University of North Carolina, revealed that multiple myeloma was particularly susceptible to VELCADE. We next teamed up with Ken Anderson at the Dana Farber Cancer Institute, to design a phase II trial to fully test this hypothesis. We also went back to the laboratory, and together with Ken's lab and scientists at Millennium, we were able to better understand some of the molecular components of what VELCADE is specifically doing in attacking multiple myeloma. This effort should be a paradigm of how to do good translational research. That is, we learn in the laboratory, take our findings to the clinical setting, learn from the patients, and return to the laboratory to gain further understanding and insights. This should be an interactive process so as to optimize the use of a new experimental agent.

MT (UK): How important is it to work with patients and patient advocate groups during this process?

Dr. Adams: Extremely important! Ken Anderson introduced us to the IMF and MMRF. We are in continuous contact with the advocacy groups, and particularly the Multiple Myleoma Research Foundation and the International Myeloma Foundation, headed by Kathy Guisti and Susie Novis respectively. They have both been marvellous individuals who have suffered as a result of this disease, directly (Kathy) or indirectly (Susie's husband) and who have committed their lives to help patients who are suffering. We have begun trials in Europe and we have been liaising with Eric Low and IMF (UK) who have provided invaluable support to the team. These people are an inspiration to me and my colleagues at Millennium, both scientists and business people, to make our resources and talents available to effect a treatment for multiple myeloma.

MT (UK): Often, gaining access to new drugs is very difficult and protracted. Do you think patients should have access to drugs such as VELCADE sooner in appropriate circumstances, outside a clinical trial setting?

Dr. Adams: We believe that the best way to serve patients to gain broad access to VELCADE is to get the drug approved through the regulatory process. We have several trials around the world which include treatments for different stages of myeloma. We are working tirelessly with the regulatory authorities to bring this drug to market as expeditiously as possible.

MT (UK): If yes, where do you think pressure should be applied to make this happen?

Dr. Adams: Pressure can be applied at all levels. Firstly, we at the company are working as quickly as possible to do everything we can to monitor and analyze the clinical data. We are also engaging the regulatory agencies to educate them about the utility of VELCADE. The National Cancer Institute is consulted regularly by these agencies. We have made presentations and lectures describing the data surrounding VELCADE. Finally, the advocacy groups themselves can play a key role as impartial lobbyists to get the attention of patients, physicians, and government bodies to provide further support and information.

MT (UK): In general terms, where do you see the treatment for myeloma heading and specifically, where do you see the role of VELCADE in the immediate and long-term future?

Dr. Adams: I think that the immediate future looks promising in myeloma. We are studying the drug in first, second, and third line treatment both as a single agent and in various combinations with other active drugs, such as dexamethasone, doxorubicin, and other therapies. We hope that these options will provide long term relief and management of the disease. We are also exploring a maintenance schedule where VELCADE would be given less frequently but for a longer period to maintain patients in remission. Eventually, we are hoping to manage the disease over many years with the goal of living a normal, high quality life for patients.

MT (UK): What's the latest news on VELCADE straight from the horse's mouth?

Dr. Adams: I am very excited about the prospects for VELCADE. It is clearly an agent that is biologically active, and we believe providing clinical benefit. The results of two phase II studies of VELCADE in patients with relapsed and refractory myeloma were presented at the annual meeting of the American Society of Hematology in Philadelphia, PA in December, 2002. In addition, on January 21, 2003, Millennium filed a New Drug Application (NDA) with the FDA, and just a few weeks later on March 10, 2003, the FDA accepted the application and granted priority review to VELCADE. On February 4, 2003, Millennium submitted a Marketing Authorization Application (MAA) for VELCADE to the European Agency for the Evaluation of Medicinal Products (EMEA), which was accepted on February 25, 2003. Importantly, we are also continuing to enroll patients in an international phase III study comparing VELCADE to high dose dexamethasone in patients with relapsed or refractory multiple myeloma.

MT (UK): Is there scope to develop derivatives of VELCADE that could be potentially even more effective?

Dr. Adams: We are working on other promising agents in the laboratory in the ubiquitin proteasome pathway which we hope will be improvements on VELCADE, but it is too soon to predict if these ideas will result in greater efficacy.

MT (UK): What are you working on in the lab at the moment?

Dr. Adams: As I mentioned above, we are mining the ubiquitin proteasome pathway to explore many other targets. The Millennium oncology franchise has a very exciting pipe-line of new targets and inhibitors which block the growth and the survival of tumors. We are attacking the fundamental machinery that leads cancer cells to survive, grow, and become metastatic. Using our knowledge of the signal transduction pathways, as well as our superior genomics technology, we feel that we are able to select the best targets to thwart cancer. The biology team at Millennium has put together a world class research effort and we will be testing some of these new compounds in clinical trials next year. Let me also remind you that we have three additional exciting drugs which are already in early stage clinical trials now. We have a growth factor inhibitor, MLN518, a Flt-3 inhibitor which targets AML; we have an antibody directed at PSMA conjugated either to a radio-label or toxin payload for the treatment of prostate cancer; and through our collaboration with Xenova, in the UK, we are testing some novel DNA interacting agents which appear very potent in animal models of lung and colon cancer.

MT (UK): What are your hopes for the future in terms of the treatment of myeloma and cancer generally? Is cure a reality?

Dr. Adams: I think it would be premature to talk about a cure for cancer. I do believe that this is an exciting time with many new prospects to successfully treat cancers, arrest their growth, and even cause remission of the tumours, while prolonging survival with better quality of life. The practical immediate goal is to manage the disease so that patients may attain longer-term survival. And yes in the long term, I am an eternal optimist and will strive, with Millennium’s support, to dare to cure myeloma and other diseases.

Note: This is an update of an interview which appeared in the Autumn 2002 issue of Myeloma Today UK.